- Overcoming drug resistance by cell-penetrating peptide-mediated delivery of a doxorubicin dimer with high DNA-binding affinity
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We describe the synthesis and characterization of a novel bioconjugate, consisting of an octaarginine cell-penetrating peptide and a highly DNA-affine doxorubicin dimer. The linkage between the two components is composed of a cleavable disulfide bond, which enables the efficient intracellular delivery of the cytotoxic payload within the reductive environment of the cytosol, mediated through glutathione. To determine the DNA-binding affinity of the dimeric drug molecule, microscale thermophoresis was applied. This is the first utilization of this method to assess the binding interactions of an anthracycline drug with nucleic acids. The cytotoxic effect of the peptide-drug conjugate, studied with drug-sensitive and doxorubicin-resistant cancer cells, demonstrates that the bioconjugate can successfully overcome drug resistance in neuroblastoma cells.
- Lelle, Marco,Freidel, Christoph,Kaloyanova, Stefka,Tabujew, Ilja,Schramm, Alexander,Musheev, Michael,Niehrs, Christof,Müllen, Klaus,Peneva, Kalina
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- Molecular imaging of cancer cells using a bacteriophage-based 129Xe NMR biosensor
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NMR imaging: Filamentous fd bacteriophage expressing antibodies recognizing the epidermal growth factor receptor (EGFR) were modified to incorporate cage-like xenon-binding molecules (CryA). The resulting contrast agent was shown to bind to an EGFR-positive cell line and detected by hyperpolarized 129Xe NMR spectroscopy using chemical exchange saturation transfer (hyperCEST, see picture). Copyright
- Palaniappan, Krishnan K.,Ramirez, R. Matthew,Bajaj, Vikram S.,Wemmer, David E.,Pines, Alexander,Francis, Matthew B.
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- An amino acid-based heterofunctional cross-linking reagent
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We describe the synthesis and characterization of a new lysine-based heterofunctional cross-linking reagent. It carries two readily available aminooxy functionalities and an activated and protected thiol group that is capable of generating reducible disulfides, the former enable bioorthogonal modification of ketones and aldehydes by the formation of an oxime bond. The efficacy of the linker was proven by coupling two doxorubicin molecules to the functionalized amino acid core and the subsequent bioconjugation of this drug conjugate with a thiolated antibody. Graphical Abstract: [Figure not available: see fulltext.]
- Lelle, Marco,Peneva, Kalina
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- Multivalency: Key Feature in Overcoming Drug Resistance with a Cleavable Cell-Penetrating Peptide-Doxorubicin Conjugate
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Multivalency is often used in biological systems, to increase affinity and specificity through avidity. This inspired us to prepare a synthetic bioconjugate that mimics natural multivalent systems. It is composed of doxorubicin and two octaarginine cell-penetrating peptides, to strengthen the electrostatic interactions between the negatively charged glycosaminoglycans of the plasma membrane and the guanidinium groups of the arginine residues. The multivalent conjugate has improved cellular uptake and cytotoxicity, compared to a peptide-drug conjugate with only one polyarginine and as a result it can overcome drug resistance in Kelly-ADR cells. The synthetic approach and the multivalent structure reported here can be used further as model systems, to gain insight into the biological interaction of cell-penetrating peptides with artificial membranes or for the preparation of more complex multimers.
- Lelle, Marco,Freidel, Christoph,Kaloyanova, Stefka,Müllen, Klaus,Peneva, Kalina
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- Ethoxyethylidene protecting group prevents N-overacylation in aminooxy peptide synthesis
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We report herein an improved synthetic route for the preparation of homogenous aminooxy peptides suitable for oxime ligation. Aminooxyacetic acid (Aoa) was protected with 1-ethoxyethylidene group (Eei) then incorporated either using PyBOP or as N-hydroxysuccinimidyl ester at N-terminal end or at a lysine side chain into model peptides in solution and on solid support. Due to the Eei protecting group, these new reagents prevent the N-overacylation side reaction in comparison with Boc-Aoa derivatives. Subsequent deprotection under mild acidic conditions gave the corresponding pure aminooxylated peptides.
- Duléry, Vincent,Renaudet, Olivier,Dumy, Pascal
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- Synthesis and biological evaluation of a siderophore-virginiamycin conjugate
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Condensation of Virginiamycin S1 (1) with aminooxyacetic acid afforded oxime 9. EDC/HOAt-mediated coupling of 9 to the N-terminus of the tripeptide of N5-hydroxy-N5-acetyl-L-ornithine, the common iron chelator in most hydr
- Lin, Yun-Ming,Helquist, Paul,Miller, Marvin J.
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- One-pot: N -glycosylation remodeling of IgG with non-natural sialylglycopeptides enables glycosite-specific and dual-payload antibody-drug conjugates
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Chemoenzymatic transglycosylation catalyzed by endo-S mutants is a powerful tool for in vitro glycoengineering of therapeutic antibodies. In this paper, we report a one-pot chemoenzymatic synthesis of glycoengineered Herceptin using an egg-yolk sialylglycopeptide (SGP) substrate. Combining this one-pot strategy with novel non-natural SGP derivatives carrying azido or alkyne tags, glycosite-specific conjugation was enabled for the development of new antibody-drug conjugates (ADCs). The site-specific ADCs and semi-site-specific dual-drug ADCs were successfully achieved and characterized with SDS-PAGE, intact antibody or ADC mass spectrometry analysis, and PNGase-F digestion analysis. Cancer cell cytotoxicity assay revealed that small-molecule drug release of these ADCs relied on the cleavable Val-Cit linker fragment embedded in the structure. These results represent a new approach for glycosite-specific and dual-drug ADC design and rapid synthesis, and also provide the structural requirement for their biologic activities.
- Tang, Feng,Yang, Yang,Tang, Yubo,Tang, Shuai,Yang, Liyun,Sun, Bingyang,Jiang, Bofeng,Dong, Jinhua,Liu, Hong,Huang, Min,Geng, Mei-Yu,Huang, Wei
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supporting information
p. 9501 - 9518
(2016/10/22)
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- Orthogonal dual-modification of proteins for the engineering of multivalent protein scaffolds
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To add new tools to the repertoire of protein-based multivalent scaffold design, we have developed a novel dual-labeling strategy for proteins that combines residue-specific incorporation of unnatural amino acids with chemical oxidative aldehyde formation at the N-terminus of a protein. Our approach relies on the selective introduction of two different functional moieties in a protein by mutually orthogonal copper-catalyzed azide-alkyne cycloaddition (CuAAC) and oxime ligation. This method was applied to the conjugation of biotin and β-linked galactose residues to yield an enzymatically active thermophilic lipase, which revealed specific binding to Erythrina cristagalli lectin by SPR binding studies.
- Mühlberg, Michaela,Hoesl, Michael G.,Kuehne, Christian,Dernedde, Jens,Budisa, Nediljko,Hackenberger, Christian P. R.
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supporting information
p. 784 - 791
(2015/06/08)
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- Versatile and Efficient Site-Specific Protein Functionalization by Tubulin Tyrosine Ligase
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A novel chemoenzymatic approach for simple and fast site-specific protein labeling is reported. Recombinant tubulin tyrosine ligase (TTL) was repurposed to attach various unnatural tyrosine derivatives as small bioorthogonal handles to proteins containing a short tubulin-derived recognition sequence (Tub-tag). This novel strategy enables a broad range of high-yielding and fast chemoselective C-terminal protein modifications on isolated proteins or in cell lysates for applications in biochemistry, cell biology, and beyond, as demonstrated by the site-specific labeling of nanobodies, GFP, and ubiquitin.
- Schumacher, Dominik,Helma, Jonas,Mann, Florian A.,Pichler, Garwin,Natale, Francesco,Krause, Eberhard,Cardoso, M. Cristina,Hackenberger, Christian P. R.,Leonhardt, Heinrich
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supporting information
p. 13787 - 13791
(2015/11/10)
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- POLYMER ENHANCEMENT OF ENZYMATIC ACTIVITY
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Provided herein are methods for enhancing enzymatic activity using certain polymers that may be optionally attached to an enzyme. The polymers may be thermally-responsive polymers, including poly N-isopropylacrylamide or poly N-isopropylmethacrylamide. The polymer may also be a copolymer with at least two different monomer residues. The monomer residues may have a structure of formula (I): wherein R1, RA and RB are as described herein. Examples of such monomer residues may include N-isopropylacrylamide (NIPAm) or N-isopropylmethacrylamide (NIPMa). The polymer may include additional monomer residues, such as aminooxy-bearing methacrylamide monomer residues that can be modified to vary the lower critical solution temperature (LCST) of the polymer.
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Paragraph 0634; 0635
(2015/12/23)
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- CARBOHYDRATE-MODIFIED GLYCOPROTEINS AND USES THEREOF
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The present invention provides immunogenic compounds which stimulate immune responses in a subject. The present invention provides compositions comprising an isolated glycoprotein antigen covalently bound at pre-existing carbohydrate residues present on the glycoprotein to a carbohydrate epitope. The present invention also provides a method to induce an immune response in a subject comprising administering the compounds of the invention. The present invention further provides methods of making the compounds of the invention and methods of using the compounds of the invention to stimulate immune responses to infectious disease agents and tumors.
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Paragraph 0147
(2014/10/04)
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- Mild bioconjugation through the oxidative coupling of ortho-aminophenols and anilines with ferricyanide
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Using a small-molecule-based screen, ferricyanide was identified as a mild and efficient oxidant for the coupling of anilines and o-aminophenols on protein substrates. This reaction is compatible with thiols and 1,2-diols, allowing its use in the creation
- Obermeyer, Allie C.,Jarman, John B.,Netirojjanakul, Chawita,El Muslemany, Kareem,Francis, Matthew B.
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p. 1057 - 1061
(2014/03/21)
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- NOVEL INDOLIC DERIVATIVES, THEIR PREPARATION PROCESSES AND THEIR USES IN PARTICULAR AS ANTIBACTERIALS
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The invention relates to the use of at least one compound of the formula (I), in which R and R3 are particularly a hydrogen atom, R1 is particularly a hydrogen atom or a methyl, ethyl or isobutyl mi group, R4, R5, R6 and R7 are independently a hydrogen atony, an alkoxyl group with 1 to 7 carbon atoms or a halogen atom, R2 is a hydrogen atom, an O? group or an OH group, B is an N-GP1 or NRc, group, GP1 being a Boc or Cbz group, and Rc is a hydrogen atom or a methyl or t-butyl group, for preparing a drug for treating conditions associated with bacterial infections, in particular for treating bacterial diseases.
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Page/Page column 49
(2010/06/19)
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- 1-Ethoxyethylidene, a new group for the stepwise SPPS of aminooxyacetic acid containing peptides
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(Chemical Equation Presented) For more than a decade, the oxime ether ligation has proven to be one of the most efficient technique for the preparation of various peptide conjugates. However, despite numerous reports, the preparation of aminooxy-containin
- Foulard, Stephanie,Rasmussen, Martin Ohsten,Razkin, Jesus,Boturyn, Didier,Dumy, Pascal
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p. 983 - 991
(2008/09/18)
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- The oxime bond formation as an efficient tool for the conjugation of ruthenium complexes to oligonucleotides and peptides
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A convenient method for the conjugation of ruthenium complex on oligonucleotides and peptides through chemoselective oxime linkage is reported. Novel Ru(II) complexes sustaining an aminooxy containing ligand were prepared and efficiently coupled with the oligonucleotides and peptides functionalized with the complementary reactive aldehyde group. The method described herein could be a useful tool for preparing a broad range of metal complex-oligonucleotide and peptide conjugates.
- Villien, Mathilde,Deroo, Stéphanie,Gicquel, Etienne,Defrancq, Eric,Moucheron, Cécile,Kirsch-De Mesmaeker, Andrée,Dumy, Pascal
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p. 11299 - 11306
(2008/03/12)
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- RADIOLABELLED INSULIN
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The invention relates to in vivo imaging agents, specifically radiolabelled insulin derivatives of formula (III); wherein X is -CO-NH- , -NH- , -O-, -NHCONH-, or -NHCSNH-, and is preferably -CO-NH- , -NH- or -O- ; Y is H, alkyl or aryl substituents; R* is
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(2008/06/13)
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- Synthesis and physical nature of fluorescent photoaffinity probe for the bioorganic studies on tautomycin, a protein phosphatase type 1 selective inhibitor
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Fluorescent photoaffinity probe, which possesses a dansyl amide functional group on the maleic moiety of tautomycin, was prepared in order to detect the trace amount of labeled peptides. The parent compound dramatically showed fluorescence quenching befor
- Kurono, Masakuni,Isobe, Minoru
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p. 452 - 453
(2007/10/03)
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- Synthesis of photoaffinity probes of tautomycin
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Two types of photoaffinity probe, which possesses a benzophenone or a diazirine photophore on the 2-position of tautomycin, were prepared in order to prove the details of binding site to PP1. These photoaffinity probes were designed on the basis of the structure-activity relationship; thus, the diacid moiety is indispensable. The selective introduction of photolabeling units on the 2-position of tautomycin was achieved through the 2-oxime of tautomycin diacid.
- Kurono, Masakuni,Shimomura, Aya,Isobe, Minoru
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p. 1773 - 1780
(2007/10/03)
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- Synthesis of an oxyamino-containing phenanthroline derivative for the efficient preparation of phenanthroline oligonucleotide oxime conjugates
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A phenanthroline derivative bearing an oxyamino linker was efficiently prepared from commercial 5-nitro-1,10-phenanthroline. The subsequent reaction with an oligonucleotide containing an aldehyde either at the 5′ end or the 3′ end afforded, in good yield, the phenanthroline-oligonucleotide conjugates through oxime bond formation.
- Deroo, Stéphanie,Defrancq, Eric,Moucheron, Cécile,Kirsch-De Mesmaeker, Andrée,Dumy, Pascal
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p. 8379 - 8382
(2007/10/03)
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